Background  Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an important focus of research in critical care medicine and basic medical science. Clarification of the key damage mechanisms and differential gene changes in ALI is essential to control the development of ALI and explore effective treatments.

  Objective   To investigate the transcriptional profile of lung histology and lung tissue at different time points in mice model of intratracheal aerosolized lipopolysaccharides (LPS) -induced ALI, and explore the potential mechanisms of injury and therapeutic targets of ALI.

  Methods   Thirty-six mice were randomly assigned to the control group and the intratracheal nebulized LPS groups (6 h, 12 h and 24 h post-injury, respectively; 9 mice in each group). Mice in the experimental group were intratracheally nebulized with 50 μL of LPS 15 mg/kg, and the control group were intratracheally nebulized with an equal volume of 0.9% sodium chloride. The histological, pathological injury and lung coefficient changes were compared among the groups, and the levels of TNF-α, IL-6 and MCP-1 in alveolar lavage fluid and serum were detected. Lung tissue transcriptome sequencing was performed in each group of mice to search for differential genes, and GO and KEGG enrichment analyses were performed for up- and down-regulated genes. Then GO functional enrichment integration and co-expression network analyses were performed for differential genes with persistent alterations.

  Results   Compared with the control group, lung histology in the LPS group showed increased inflammatory cell infiltration, and pulmonary vascular edema with a small amount of hemorrhage. The lung injury score and lung coefficient score gradually increased and appeared the most serious injury at 24 h. The expression levels of TNF-α, IL-6, and MCP-1 increased significantly, and there was a certain difference between the expression in BALF and plasma (P<0.01); Transcriptomics suggested that there were 1 550 up-regulated genes and 1 670 down-regulated genes in LPS 12h group, while 1 312 up-regulated genes and 1 139 down-regulated genes in LPS 24 h group. KEGG enrichment analysis showed that the differential genes were involved in inflammatory response, regulation of genetic information, signal transduction and other pathways. GO enrichment analysis showed that the differential genes were concentrated in the regulation of cytokine production, immune response, leukocyte immune-mediated, immune regulation and leukocyte migration (up-regulated genes), while blood circulation, signaling, nerve synapses, and muscle contraction (down-regulated genes). PPI analysis suggested that key genes persistently up-regulated genes included Tnf , IL-1β, Ifn-γ, Ccl2, Ccl5, Nod2, Tlr2, Lgals9, while key genes persistently down-regulated included Cav1, Sulf1, Sox4, Tgf-β, Apoe, Tek.

  Conclusion   We have established a stable and reliable mouse model of intratracheal nebulization LPS 12 h induced acute lung injury. Tnf, IL-1β, Ifn-γ, Ccl2, Ccl5, Nod2, Tlr2, Lgals9 may be key regulators and target genes in the immune and inflammatory response in ALI.